US5767139A - Indoles which have steroid 5-α reductase inhibitory activity - Google Patents
Indoles which have steroid 5-α reductase inhibitory activity Download PDFInfo
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- US5767139A US5767139A US08/256,734 US25673494A US5767139A US 5767139 A US5767139 A US 5767139A US 25673494 A US25673494 A US 25673494A US 5767139 A US5767139 A US 5767139A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
Definitions
- This invention relates to indole derivatives which have steroid 5 ⁇ -reductase inhibitory activity.
- this invention relates to indoles, their preparation and their use as testosterone-5 ⁇ -reductase inhibitors.
- the androgen class of steroidal hormones is responsible for the difference in the physical characteristics of males and females. Of all the organs that produce androgens, the testes produce these hormones in the greatest amounts. Over-production of these hormones in the body results in many undesirable physical manifestations and disease states, e.g. acne vulgaris, alopecia, seborrhoea, female hirsutism, benign prostatic hypertrophy and male pattern baldness.
- Testosterone is therefore the prohormone of 5 ⁇ -dihydrotestosterone which is formed locally in the above organs by the action of testosterone-5 ⁇ -reductase.
- the presence of elevated levels of dihydrotestosterone in many disease states has therefore focussed attention on the synthesis of testosterone 5 ⁇ -reductase inhibitors.
- Testosterone 5 ⁇ -reductase inhibitors may also be useful in the treatment of human prostate adenocarcinomas.
- EP-A-0458207 discloses indole derivatives with testosterone 5 ⁇ -reductase inhibitory activity.
- the present invention provides compounds of the formula: ##STR2## and pharmaceutically acceptable salts thereof, wherein
- X is O, NH, N(C 1 -C 4 alkyl), direct link, C 1 -C 4 alkylene, C 2 -C 4 alkenylene or C 2 -C 4 alkynylene, said alkylene, alkenylene and alkynylene being optionally substituted by C 1 -C 4 alkyl or aryl;
- Y is methylene, C 2 -C 6 alkylene optionally interrupted by O, C 2 -C 6 alkenylene or C 2 -C 6 alkynylene, all of which may be optionally substituted by C 1 -C 6 alkyl, or is a group of the formula: ##STR3## wherein m and n are each independently selected from O and an integer of from 1 to 5, with the proviso that the sum of m and n is not greater than 5, and p is an integer of from 2 to 6;
- R is H, OH, halo, C 1 -C 4 alkyl or C 1 -C 4 alkoxy;
- R 1 , R 2 , R 3 and R 4 are each independently selected from H, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, OH, halo, --CF 3 , --CO 2 (C 1 -C 4 alkyl) , --CONH 2 , --CONH(C 1 -C 4 alkyl) and --CON(C 1 -C 4 alkyl) 2 ;
- R 5 is --COOH, --COOR 7 , --CONR 8 R 9 or tetrazol-5-yl;
- R 6 is ##STR4##
- R 7 is a biolabile ester-forming group;
- R 8 and R 9 are each independently selected from H and C 1 -C 4 alkyl;
- R 10 , R 11 and R 12 are each independently selected from H, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, --OH, halo and halo(C 1 -C 4 alkyl);
- R 13 and R 14 are each independently selected from H, C 1 -C 10 alkyl, C 1 -C 10 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, --CO 2 (C 1 -C 4 alkyl), --CONR 8 R 9 , --CN, halo(C 1 -C 6 alkyl), aryl and heteroaryl, said alkyl and alkoxy groups being optionally substituted by C 1 -C 6 alkoxy, C 3 -C 7 cycloalkyl, --OH, --CO 2 (C 1 -C 4 alkyl), --CONR 8 R 9 , --CN, aryl, aryloxy or heteroaryl, and said alkenyl and alkynyl groups being optionally substituted by aryl, with the proviso that R 13 and R 14 are not both H, or R 13 and R 14 , taken together with the carbon atom to which they are attached,
- aryl used in the definitions of X, R 13 and R 14 means phenyl optionally substituted by C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, OH, halo, halo(C 1 -C 6 alkyl), nitro, amino, C 2 -C 6 alkanamido, C 2 -C 6 alkanoyl, --CO 2 (C 1 -C 4 alkyl), phenyl, phenyl(C 1 -C 4 )alkoxy or --(CH 2 ) q CONR 8 R 9 wherein q is O or an integer of from 1 to 4;
- heteroaryl used in the definitions of R 13 and R 14 means a five- or six-membered heteroaromatic group which contains from 1 to 4 heteroatoms each independently selected from N, O and S and which is optionally substituted by C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halo, --OH or halo-(C 1 -C 4 alkyl).
- Alkyl and alkoxy groups containing three or more carbon atoms and alkenyl, alkanamido and alkanoyl groups containing four or more carbon atoms may be straight- or branched-chain.
- halo means fluoro, chioro, bromo or iodo.
- biolabile ester-forming group is well understood in medicinal chemistry as meaning a group which forms an ester which can be readily cleaved in vivo to liberate the corresponding acid of the formula (I) wherein R 5 is --COOH.
- a number of such ester groups are well-known, for example in the penicillin area or in the case of the angiotensin-converting enzyme (ACE) inhibitor antihypertensive agents.
- ACE angiotensin-converting enzyme
- Esters of the formula (I) wherein R 5 is --COOR 7 wherein R 7 is C 1 -C 6 alkyl are steroid 5 ⁇ -reductase inhibitors per se but, in general, esters where R 7 is a biolabile ester-forming group are useful as pro-drugs to provide compounds of the formula (I) wherein R 5 is --COOH in vivo following oral administration.
- esters are also useful as intermediates for the preparation of compounds of the formula (I) wherein R 5 is --COOH.
- biolabile ester-forming groups are alkyl, alkanoyloxyalkyl (including alkyl, cycloalkyl or aryl substituted derivatives thereof), arylcarbonyl-oxyalkyl (including aryl substituted derivatives thereof), aryl, arylalkyl, indanyl and haloalkyl: wherein alkanoyl groups have from 2 to 8 carbon atoms, alkyl groups have from 1 to 8 carbon atoms and aryl means phenyl or naphthyl, both of which may be optionally substituted by C 1 -C 4 alkyl, C 1 -C 4 alkoxy or halo.
- Alkyl, alkanoyl and alkoxy groups can, where appropriate, be straight- or branched-chain.
- biolabile ester-forming groups are C 1 -C 6 alkyl (e.g. methyl, ethyl, n-propyl, isopropyl), benzyl, 1-(2,2-diethylbutyryloxy)ethyl, 2-ethyl-propionyloxymethyl, 1-(2-ethylpropionyloxy)ethyl, 1-(2,4-dimethylbenzoyloxy)ethyl, ⁇ -benzoyloxybenzyl, 1-(benzoyloxy)ethyl, 2-methyl-1-propionyloxy-1-propyl, 2,4,6-trimethylbenzoyloxymethyl, 1-(2,4,6-trimethyl-benzoyloxy)ethyl, pivaloyloxymethyl, phenethyl, phenpropyl, 2,2,2-trifluoroethyl, 1- or 2-naphthyl, 2,4-dimethylphenyl, 4-t-butylphenyl
- the pharmaceutically acceptable salts of the compounds of the formula (I) include suitable acid addition and base salts thereof.
- Suitable acid addition salts are formed from acids which form non-toxic salts and examples thereof are the hydrochloride, hydrobromide, hydroiodide, sulphate, bisulphate, phosphate, hydrogen phosphate, acetate, maleate, fumarate, lactate, tartrate, citrate, gluconate, benzoate, methanesulphonate, benzenesulphonate and p-toluenesulphonate salts.
- Suitable base salts are formed from bases which form non-toxic salts and examples thereof are the aluminium, calcium, lithium, magnesium, potassium, sodium, zinc, N-benzyl-N-(2-phenylethyl)amine, 1-adamantylamine and diethanolamine salts.
- Preferred base salts are the sodium, potassium, N-benzyl-N-(2-phenylethyl)amine and 1-adamantylamine salts.
- aryl means phenyl optionally substituted by up to 3 substituents and preferably means phenyl optionally substituted by 1 or 2 substituents.
- heteroaryl means pyrrolyl, furyl, thienyl, imidazolyl, thiazolyl, triazolyl, pyridinyl, pyrimidinyl, pyridazinyl or pyrazinyl, all of which may be optionally substituted by C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halo, --OH or halo(C 1 -C 4 alkyl).
- X is direct link or C 1 -C 4 alkylene. More preferably X is direct link or methylene. Most preferably X is direct link.
- Y is C 1 -C 6 alkylene. More preferably Y is ethylene, propylene or butylene. Most preferably Y is propylene.
- R is H or C 1 -C 4 alkyl. More preferably R is H or methyl. Most preferably R is H.
- R 1 , R 2 , R 3 and R 4 are each H.
- R 5 is --COOH or --COOR 7 where R 7 is as defined for a compound of the formula (I). More preferably R 5 is --COOH or --COO(C 1 -C 6 alkyl). Yet more preferably R 5 is --COOH or --COOC 2 H 5 . Most preferably R 5 is --COOH.
- R 6 is ##STR5## wherein R 10 to R 14 are as previously defined for a compound of the formula (I).
- R 10 , R 11 and R 12 are each H.
- R 13 and R 14 are each independently selected from H, C 1 -C 10 alkyl optionally substituted by C 1 -C 6 alkoxy, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, aryl and heteroaryl, with the proviso that R 13 and R 14 are not both H, or R 13 and R 14 , taken together with the carbon atom to which they are attached, represent optionally benzo-fused spiro(C 3 -C 8 )cycloalkane, optionally substituted by --CN or aryl. More preferably R.sup.
- R 13 and R 14 are each independently selected from H, C 1 -C 10 alkyl optionally substituted by C 1 -C 6 alkoxy, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, phenyl optionally substituted by C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halo, halo(C 1 -C 6 alkyl) or phenyl(C 1 -C 4 )alkoxy, thienyl and furyl, with the proviso that R 13 and R 14 are not both H, or R 13 and R 14 , taken together with the carbon atom to which they are attached, represent optionally benzo-fused spiro(C 5 -C 7 ) cycloalkane, optionally substituted by --CN or phenyl.
- R 13 and R 14 are each independently selected from H, methyl, ethyl, n-propyl, n-butyl, t-butyl, 3-methoxyprop-1-yl, 1-propynyl, cyclohexyl, phenyl, 4-methylphenyl, 4-ethylphenyl, 4-(n-propyl)phenyl, 4-(2-methylpropyl)phenyl, 3,4-dimethylphenyl, 4-fluorophenyl, 2-chlorophenyl, 4-chlorophenyl, 3,4-dichlorophenyl, 4-methoxyphenyl, 4-trifluoromethylphenyl, 4-benzyloxyphenyl, cyclohexyl, 2-thienyl and 2-furyl, with the proviso that R 13 and R 14 are not both H, or R 13 and R 14 , taken together with the carbon atom to which they are attached, represent spirocyclohexane,
- a compound of the formula (I) may contain one or more asymmetric carbon atoms and/or one or more non-aromatic carbonp13 carbon double bonds and may therefore exist in two or more stereoisomeric forms.
- the present invention includes both the individual stereoisomers of the compounds of the formula (I) together with mixtures thereof. Separation of diastereoisomers or cis and trans isomers may be achieved by conventional techniques, e.g. by fractional crystallisation, chromatography or H.P.L.C. of a stereoisomeric mixture of a compound of the formula (I) or a suitable salt or derivative thereof.
- An individual enantiomer of a compound of the formula (I) may also be prepared from a corresponding optically pure intermediate or by resolution, such as by H.P.L.C. of a racemate using a suitable chiral support or by fractional crystallisation of the diastereoisomeric salts formed by reaction of a racemate with a suitable optically active acid or base.
- Preferred compounds of the formula (I) are 4- 3-( 2-methyl-2-(4- 2-methylpropyl!phenyl)-1,3-benzodioxolan-5-yl!carbonyl)indol-1-yl!butanoic acid and ethyl 4- 3-( 2-methyl-2-(4- 2-methylpropyl!phenyl)-1,3-benzodioxolan-5-yl!carbonyl)indol-1-yl!butanoate and the pharmaceutically acceptable salts thereof.
- Particularly preferred compounds of the formula (I) are (-)-4- 3-( 2-methyl-2-(4- 2-methylpropyl!phenyl)-1,3-benzodioxolan-5-yl!carbonyl)indol-1-yl!butanoic acid and (-)-ethyl 4- 3-( 2-methyl-2-(4- 2-methylpropyl)phenyl)-1,3-benzodioxolan-5-yl)carbonyl)indol-1-yl!butanoate and the pharmaceutically acceptable salts thereof.
- Preferred intermediates used in the preparation of the above preferred compounds of the formula (I) are 2-methyl-2- 4-(2-methylpropyl)phenyl!-1,3-benzodioxolane-5-carboxylic acid, (-)-2-methyl-2-(4-(2-methylpropyl)-phenyl!-1,3-benzodioxolane-5-carboxylic acid and the (-)- ⁇ -methylbenzylamine salt thereof, 3-( 2-methyl-2-(4- 2-methylpropyl!phenyl)-1,3-benzodioxolan-5-yl!carbonyl)indole and (-)-3-( 2-methyl-2-(4- 2-methylpropyl!phenyl)-1,3-benzodioxolan-5-yl!carbonyl)indole.
- the compounds of formula (I) provided by the invention may be prepared by the following methods:
- ester-forming groups that may be cleaved to provide the corresponding carboxylic acid are known to the skilled man, see, e.g., T. W. Greene, "Protective Groups in Organic Synthesis", Wiley-Interscience (1981).
- R 15 is an ester-forming group that may be removed by hydrolysis, e.g. a biolabile ester-forming group as previously defined such as C 1 -C 6 alkyl (i.e. a compound of the formula (I) wherein R 5 is --COOR 7 ), the hydrolysis may be carried out under acidic or basic conditions, e.g. using an aqueous solution of either a suitable mineral acid or a suitable inorganic base. Preferably the hydrolysis is carried out under basic conditions.
- a biolabile ester-forming group as previously defined such as C 1 -C 6 alkyl
- the hydrolysis may be carried out under acidic or basic conditions, e.g. using an aqueous solution of either a suitable mineral acid or a suitable inorganic base.
- the hydrolysis is carried out under basic conditions.
- an ester of the formula (II) is treated with an aqueous solution of a suitable base, e.g. sodium or potassium hydroxide, and in the presence of a suitable organic co-solvent, e.g. tetrahydrofuran or a C 1 -C 4 alkanol (e.g. methanol or ethanol) or a combination thereof.
- a suitable base e.g. sodium or potassium hydroxide
- a suitable organic co-solvent e.g. tetrahydrofuran or a C 1 -C 4 alkanol (e.g. methanol or ethanol) or a combination thereof.
- the hydrolysis is typically carried out at from room temperature to the reflux temperature.
- the product is obtained as a base salt which may be converted to the carboxylic acid by acidification in the work-up procedure.
- R 15 is an ester-forming group that may be removed by reduction, e.g. benzyl
- the reduction may be carried out by catalytic hydrogenation using, e.g., palladium-on-charcoal, as the catalyst.
- the hydrolysis may be carried out under acidic or basic conditions, e.g. using an aqueous solution of either a suitable mineral acid, e.g. hydrochloric or sulphuric acid, or a suitable inorganic base, e.g. sodium or potassium hydroxide, at from room temperature to the reflux temperature.
- a suitable mineral acid e.g. hydrochloric or sulphuric acid
- a suitable inorganic base e.g. sodium or potassium hydroxide
- the hydrolysis may be carried out under acidic or basic conditions, e.g. using an aqueous solution of either a suitable acid, e.g. hydrochloric or acetic acid, or a suitable inorganic base, e.g. sodium or potassium hydroxide, at from room temperature to the reflux temperature.
- a suitable acid e.g. hydrochloric or acetic acid
- a suitable inorganic base e.g. sodium or potassium hydroxide
- the hydrolysis may be carried out under acidic or basic conditions, e.g. using an aqueous solution of either a suitable acid, e.g. hydrochloric or sulphuric acid, or a suitable inorganic base, e.g. sodium or potassium hydroxide, at from room temperature to the reflux temperature.
- a suitable acid e.g. hydrochloric or sulphuric acid
- a suitable inorganic base e.g. sodium or potassium hydroxide
- the compounds of the formula (I) wherein R 5 is --COOH and X, Y, R, R 1 to R 4 and R 6 are as previously defined for a compound of the formula (I) may be prepared by acidic hydrolysis of a compound of the formula: ##STR10## wherein X, Y, R, R 1 to R 4 and R 6 are as previously defined for a compound of the formula (I) and R 17 and R 18 taken together represent ethylene, said ethylene being optionally substituted by phenyl or C 1 -C 4 alkyl (preferably methyl).
- R 17 and R 18 taken together represent --CH 2 C(CH 3 ) 2 --.
- the hydrolysis may be carried out using an aqueous solution of a suitable acid such as hydrochloric acid at from room temperature to the reflux temperature.
- a suitable acid such as hydrochloric acid
- the compounds of the formula (I) wherein R 5 is --CONH 2 and X, Y, R, R 1 to R 4 and R 6 are as previously defined for a compound of the formula (I) may be prepared by partial hydrolysis of a compound of the formula (IV) wherein X, Y, R, R 1 to R 4 and R 6 are as previously defined for a compound of the formula (I).
- the hydrolysis may be carried out using concentrated sulphuric acid at from 0° C. to room temperature.
- the reaction may be carried out under classical esterification conditions such as by using an excess of the alcohol and with acid catalysis, e.g. by sulphuric acid or p-toluenesulphonic acid, at from room temperature to the reflux temperature.
- acid catalysis e.g. by sulphuric acid or p-toluenesulphonic acid
- the water generated during the reaction may be removed by azeotropic distillation or by the use of a dehydrating agent or a molecular sieve.
- the esterification may also be carried out by reacting the acid with the alcohol in the presence of a dehydrating agent, e.g. dicyclohexylcarbodiimide or diethylazodicarboxylate/triphenylphosphine (see 0. Mitsunobu, Synthesis, 1981, 1).
- a dehydrating agent e.g. dicyclohexylcarbodiimide or diethylazodicarboxylate/triphenylphosphine (see 0. Mitsunobu, Synthesis, 1981, 1).
- esterification may be carried out by first forming an activated ester or imidazolide derivative of the carboxylic acid, followed by reaction of the activated ester or imidazolide in situ with the alcohol of the formula R 7 OH.
- An activated ester may be formed by reacting the carboxylic acid with 1-hydroxybenzotriazole in the presence of a suitable dehydrating agent, e.g. 1-(3-N,N-dimethylaminopropyl)-3-ethylcarbodiimide, and in a suitable solvent, e.g. dichloromethane, at room temperature.
- An imidazolide may be formed by reacting the carboxylic acid with 1,1'-carbonyldiimidazole in a suitable solvent, e.g. dichloromethane, at room temperature.
- the reaction may be carried out in the presence of an acid acceptor, e.g. pyridine, and in a suitable solvent, e.g. dichloromethane, at from 0° C. to room temperature.
- an acid acceptor e.g. pyridine
- a suitable solvent e.g. dichloromethane
- the compounds of the formula (I) wherein R 5 is --COOR 7 wherein X, Y, R, R 1 to R 4 , R 6 and R 7 are as previously defined for a compound of the formula (I) may be prepared by reaction of a base salt of a compound of the formula (I) wherein R 5 is --COOH and X, Y, R, R 1 to R 4 and R 6 are as previously defined for a compound of the formula (I) (i.e. a carboxylate base salt) with a compound of the formula R 7 Z 2 wherein R 7 is as previously defined for a compound of the formula (I) and Z z is a suitable leaving group, e.g.
- halo preferably bromo or iodo, or p-toluenesulphonyloxy.
- Preferred base salts of a compound of the formula (I) for use in this method include the sodium and potassium salts.
- the reaction may be carried out in a suitable solvent, e.g. dimethylformamide or tetrahydrofuran, at from room temperature to the reflux temperature.
- the compounds of the formula (I) wherein R 5 is --CONR 8 R 9 and X, Y, R, R 1 to R 4 , R 6 , R 8 and R 9 are as previously defined for a compound of the formula (I) may be prepared by reaction of a compound of the formula (I) wherein R 5 is --COOH and X, Y, R, R 1 to R 4 and R 6 are as previously defined for a compound of the formula (I) with an amine of the formula R 8 R 9 NH wherein R 8 and R 9 are as previously defined for this method in the presence of a dehydrating agent, e.g. dicyclohexylcarbodiimide.
- the reaction may be carried out in a suitable organic solvent, e.g. dichloromethane, at from room temperature to the reflux temperature.
- reaction may be carried out by first forming an activated ester or imidazolide derivative of the carboxylic acid, followed by reaction of the activated ester or imidazolide in situ with the amine of the formula R 8 R 9 NH. Suitable procedures for the formation of an activated ester or imidazolide are described in method (7)
- the compounds of the formula (I) wherein R 10 is --CONR 8 R 9 and X, Y, R, R 1 to R 4 , R 6 , R 8 and R 9 are as previously defined for a compound of the formula (I) may be prepared by reaction of a compound of the formula (VI) wherein X, Y, R, R 1 to R 4 , R 6 and Z 1 are as previously defined for a compound of the formula (VI) with an amine of the formula R 8 R 9 NH wherein R 8 and R 9 are as previously defined for this method.
- the reaction may be carried out in the presence of an acid acceptor, e.g. pyridine, and in a suitable solvent, e.g. dichloromethane, at from 0° C. to room temperature.
- R 5 is --COOR 7 ), or p-nitrophenyl
- X, Y, R, R 1 to R 4 and R 6 are as previously defined for a compound of the formula (I) with an amine of the formula R 8 R 9 NH wherein R 8 and R 9 are as previously defined for this method.
- the reaction may be carried out in a suitable solvent, e.g. a C 1 -C 4 alkanol, at from room temperature to the reflux temperature.
- the reaction is usually carried using an excess of the amine and in a sealed reaction vessel.
- a biolabile ester-forming group as previously defined such as C 1 -C 6 alkyl, or NR 8 R 9 wherein R 8 and R 9 are as previously defined for this method, as appropriate.
- the hydrolysis may be carried out using a suitable acid, e.g. hydrochloric acid or p-toluenesulphonic acid, in the presence of water.
- the compounds of the formula (VII) may be prepared by first forming the corresponding ketal of a compound of the formula (VIII) wherein X, R, R 1 to R 4 and R 6 are as previously defined for this method, by reacting with the appropriate alcohol under acidic conditions, e.g. see T. W. Greene, "Protective Groups in Organic Synthesis", Wiley-Interscience (1981), followed by N-alkylation of the ketal by a similar procedure to that described in method (14) for alkylation of a compound of the formula (VIII).
- All the compounds of the formula (I) wherein X, Y, R and R 1 to R 6 are as previously defined for a compound of the formula (I) may be prepared by alkylation of a base salt (i.e. the N-deprotonated form) of a compound of the formula: ##STR13## wherein X, R, R 1 to R 4 and R 6 are as previously defined for a compound of the formula (I) with a compound of the formula Z 3 --Y--COOR 7 , Z 3 --Y--CONR 8 R 9 or a base salt of a compound of the formula Z 3 --Y--COOH wherein Y, R 7 , R 8 and R 9 are as previously defined for a compound of the formula (I) and Z 3 is a leaving group, e.g.
- the preferred base salts of the compounds of the formula Z 3 --Y--COOH include the alkali metal and alkaline earth metal salts, e.g. the sodium and potassium salts.
- the preferred base salts of the compounds of the formula (VIII) include the alkali metal salts, e.g. the sodium and potassium salts.
- the reaction may be performed by initial deprotonation of a compound of the formula (VIII) with a suitable base, e.g. sodium hydride or potassium carbonate, followed by reaction of the resulting anion with a compound of the formula Z 3 --Y--COOR 7 , Z 3 --Y--CONR 8 R 9 or a base salt of a compound of the formula Z 3 --Y--COOH, as required.
- a suitable solvent e.g. N,N-dimethylformamide, tetrahydrofuran or 2-butanone, at from 0° C. to the reflux temperature.
- reaction may be carried out under phase transfer conditions where a suitable base is sodium or potassium hydroxide.
- X and R 6 are as previously defined for this method and Z 4 is a leaving group, e.g. halo, preferably chloro, and in the presence of a Lewis acid where R is not OH and optionally in the presence of a Lewis acid where R is OH.
- Suitable Lewis acids include aluminium chloride and diethylaluminium chloride.
- the reaction may be carried out in a suitable solvent, e.g. toluene, at from room temperature to the reflux temperature.
- a suitable solvent e.g. toluene
- the preferred base salts of an indole of the formula (X) include the alkali metal and alkaline earth metal salts, e.g. the sodium and potassium salts.
- an indole of the formula (IX) or a base salt of an indole of the formula (X) should first be treated with one equivalent of a suitable base, e.g. calcium hydroxide, to form an enolate salt which may then be acylated with a compound of the formula (XI), optionally in the presence of a Lewis acid. Incorporation of an acidification step in the work-up procedure affords a compound of the formula (I) wherein R is OH.
- a suitable base e.g. calcium hydroxide
- the reaction may be carried out by ozonolysis or by treatment with aqueous potassium permanganate solution.
- R 6 is as previously defined for this method.
- a similar esterification procedure to any one of those described in method (7) may be used.
- the compounds of the formula (I) wherein X, Y, R and R 1 to R 6 are as defined for a compound of the formula (I) in method (17) may be prepared by reaction of a compound of the formula: ##STR18## wherein Y, R, R 1 to R 4 , R 7 , R 8 and R 9 are as previously defined for this method and Z 6 is a leaving group, e.g. chloro or bromo, with a compound of the formula (XIV) wherein R 6 is as previously defined for this method.
- the reaction may be carried out in the presence of an acid acceptor, e.g. pyridine, and in a suitable solvent, e.g. dichloromethane, at from 0° C. to room temperature.
- an acid acceptor e.g. pyridine
- a suitable solvent e.g. dichloromethane
- R 6 is as previously defined for this method.
- the reaction may be carried out in the presence of a suitable dehydrating agent, e.g. dicyclohexylcarbodiimide, and in a suitable organic solvent, e.g. dichloromethane, at from room temperature to the reflux temperature.
- a suitable dehydrating agent e.g. dicyclohexylcarbodiimide
- a suitable organic solvent e.g. dichloromethane
- reaction may be carried out by first forming an activated ester or imidazolide derivative of the carboxylic acid, followed by reaction of the activated ester or imidazolide in situ with the amine. Suitable procedures for the formation of an activated ester or imidazolide are described in method (7).
- the compounds of the formula (I) wherein X, Y, R and R 1 to R 6 are as defined for a compound of the formula (I) in method (19) may be prepared by reaction of a compound of the formula (XV), wherein Y, R, R 1 to R 4 , R 7 , R 8 and R 9 are as previously defined for this method and Z 6 is as previously defined for a compound of the formula (XV) with an amine of the formula (XVI) wherein R 6 is as previously defined for this method.
- the reaction may be carried out in the presence of an acid acceptor, e.g. pyridine, and in a suitable solvent, e.g. dichloromethane, at from 0° C. to room temperature.
- the compounds of the formula (I) wherein X is NH or N(C 1 -C 4 alkyl), R 5 is --COOH or --CONR 8 R 9 and Y, R, R 1 to R 4 , R 6 , R 8 and R 9 are as defined for a compound of the formula (I) may be prepared by reaction of a compound of the formula: ##STR19## or a base salt thereof, wherein Y, R, R 1 to R 4 , R 8 and R 9 are as previously defined for this method and R 23 is a suitable ester-forming group, e.g. C 1 -C 4 alkyl or p-nitrophenyl, with an amine of the formula (XVI) wherein R 6 is as previously defined for this method.
- the reaction may be carried out in a suitable solvent, e.g. a C 1 -C 4 alkanol, at from room temperature to the reflux temperature.
- a suitable solvent e.g. a C 1 -C 4 alkanol
- the compounds of the formula (I) wherein R 5 is --COOH and X, Y, R, R 1 to R 4 and R 6 are as previously defined for a compound of the formula (I) may be prepared by oxidation of a compound of the formula: ##STR20## wherein X, Y, R, R 1 to R 4 and R 6 are as previously defined for this method.
- a suitable oxidising agent for this purpose is chromium trioxide in pyridine.
- the compounds of the formula (I) wherein R 5 is --COOH, X is direct link and Y, R, R 1 to R 4 and R 6 are as previously defined for a compound of the formula (I) may be prepared by oxidation of a compound of the formula: ##STR21## or a base salt thereof, wherein R 24 is H or OH and Y, R, R 1 to R 4 and R 6 are as defined for a compound of the formula (I).
- a suitable oxidising agent for this purpose is chromium trioxide-pyridine complex.
- the oxidation may alternatively be carried out on a compound of the formula (XX) wherein R 24 is H using 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) as the oxidising agent.
- DDQ 2,3-dichloro-5,6-dicyano-1,4-benzoquinone
- the oxidation may alternatively be carried out on a compound of the formula (XX) wherein R 24 is OH using manganese dioxide as the oxidising agent or under the conditions of the Swern oxidation reaction.
- the starting materials of the formula (XIX) or (XX) wherein R 24 is H may be prepared by reacting the corresponding 1H-indole-3-magnesium halide derivative with a compound of the formula:
- R 6 is as previously defined for this method and Z 7 is halo, preferably chloro or bromo, followed by N-alkylation of the indole by a similar procedure to that described in method (14).
- the starting materials of the formula (XIX) or (XX) wherein R 24 is OH may be prepared by reacting the corresponding 1H-indole-3-magnesium halide derivative with a compound of the formula:
- R 6 is as previously defined for this method followed by N-alkylation of the indole by a similar procedure to that described in method (14).
- the compounds of the formula (I) wherein X is C 2 -C 4 alkylene optionally substituted by C 1 -C 4 alkyl or aryl, and Y, R, R 1 to R and R 6 are as defined for a compound of the formula (I) may be prepared by reduction of a compound of the formula (I) wherein X is C 2 -C 4 alkenylene or C 2 -C 4 alkynylene, said alkenylene and alkynylene being optionally substituted by C 1 -C 4 alkyl or aryl, and Y, R, R 1 to R 4 and R 6 are as previously defined for a compound of the formula (I).
- the reduction may be carried out using hydrogen in the presence of a suitable catalyst, e.g. palladium-on-charcoal, and in a suitable solvent, e.g. ethanol or ethyl acetate, at from room temperature to the reflux temperature and at a pressure of from one to five atmospheres.
- a suitable catalyst e.g. palladium-on-charcoal
- a suitable solvent e.g. ethanol or ethyl acetate
- R 13 and R 14 are as defined for a compound of the formula (I).
- a suitable organic solvent e.g. toluene
- a catalytic amount of a suitable acid e.g. p-toluenesulphonic acid.
- a suitable acid e.g. p-toluenesulphonic acid.
- the dimethyl ketal or acetal is used and the reaction is carried out in a Dean-Stark apparatus;
- R 13 and R 14 are as previously defined for a compound of the formula (I).
- the compounds of the formulae (XXIII) and (XXV) are heated together in the absence of solvent at about 150° C. to provide the product;
- R 13 and R 14 are as previously defined for a compound of the formula (I).
- the preferred C 1 -C 4 alkyl group in (XXVI) is methyl.
- a suitable organic solvent e.g. toluene
- mercury (II) catalysis e.g. by using mercury (II) chloride
- R 13 and R 14 are as defined for a compound of the formula (I).
- a suitable organic solvent e.g. toluene
- a suitable acid catalyst e.g. hydrochloric acid or sulphuric acid, and preferably in a Dean-Stark apparatus;
- R 13 and R 14 are as defined for a compound of the formula (I).
- the reaction is typically carried out in a suitable aprotic organic solvent, e.g. dichloromethane, at room temperature and in the presence of t-butyl hypochlorite.
- a suitable aprotic organic solvent e.g. dichloromethane
- the compounds of the formula (XXVIII) may be prepared from the corresponding hydrazone derivatives by oxidation; or
- R 13 and R 14 are as defined for this procedure (f).
- the reaction is typically carried out in a suitable organic solvent, e.g. toluene, in the presence of an acid catalyst, e.g. p-toluenesulphonic, hydrochloric or sulphuric acid, at from room temperature to the reflux temperature of the solvent.
- a suitable enol ether derivatives for use in this procedure (f) may be derived from a compound of the formula (XXVIIA) by reaction with a suitable tri(C 1 -C 4 alkyl)orthoformate, e.g. trimethyl- orthoformate, in the presence of an acid catalyst, e.g. p-toluenesulphonic acid.
- any one of methods (25)(a) to (f) may also be carried out using a suitable base, e.g. sodium, salt of a compound of the formula (XXIII) wherein R 5 is --COOH, i.e. a carboxylate salt, followed by an acidification step in the work-up procedure.
- a suitable base e.g. sodium, salt of a compound of the formula (XXIII) wherein R 5 is --COOH, i.e. a carboxylate salt
- the starting materials of the formula (XXIII) may be prepared by acidic hydrolysis of a compound of the formula (I) wherein R 13 and R 14 are both phenyl and otherwise R 6 and X, Y, R and R 1 to R 5 are as defined for a compound of the formula (I). In a typical procedure the hydrolysis is carried out using aqueous acetic acid and the reaction is heated under reflux.
- a pharmaceutically acceptable salt of a compound of the formula (I) may be readily prepared by mixing together solutions of a compound of the formula (I) and the desired acid or base, as appropriate.
- the salt may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent.
- the compounds of the formula (I) are steroid 5 ⁇ -reductase inhibitors and therefore they are useful in the curative or prophylactic treatment of diseases or conditions such as acne vulgaris, alopecia, seborrhoea, female hirsutism, benign prostatic hypertrophy and male pattern baldness.
- Certain compounds of the formula (I) are also useful for the treatment of human prostate adenocarcinomas.
- the compounds of the formula (I) may be tested in vitro for steroid 5 ⁇ -reductase inhibitory activity using prostate tissue from rats or humans as follows:
- the compounds of the formula (I) may be tested for their potency in inhibiting rat steroid 5 ⁇ -reductase using ventral prostate tissue from male rats. In determining inhibitory potency against rat prostatic 5 ⁇ -reductase the following procedure was employed:
- Rat prostates were minced into small pieces.
- the tissue was homogenised in Buffer A (20 mM sodium phosphate, pH 6.5, buffer containing 0.32M sucrose and 1 mM dithiothreitol) with a Brinkman Polytron (Kinematica, Luzern, GmBH), and then homogenised with a motor driven (1000 rpm) Potter Elvehjem (teflon-to-glass) homogeniser.
- Prostate particles were obtained by centrifugation at 105,000 G for 60 minutes.
- the pellet was washed in 4 volumes of Buffer A and recentrifuged at 105,000 G.
- the resulting pellet was dispersed in Buffer A (1 ml per g of prostate tissue originally used) with a motor driven Potter Elvehjem homogeniser as described above.
- the particulate suspension was stored as 1 ml samples at -70° C.
- the radiochemical content in the bands of the substrate (testosterone) and the product (5 ⁇ -dihydrotestosterone) were determined with a RITA Radio TLC Analyser (Raytest Instruments Ltd., Sheffield, U.K.). The percent of recovered radiolabel converted to 5 ⁇ -dihydrotestosterone was calculated and used to determine enzyme activity. All incubations were conducted so that no more than 15% of substrate (testosterone) was converted to product.
- the compounds of the formula (I) may be tested for their potency in inhibiting human steroid 5 ⁇ -reductase using tissue from hyperplastic human prostates. In determining inhibitory potency against human prostatic 5 ⁇ -reductase the following procedure was employed:
- Frozen human prostate tissue was pulverised in liquid nitrogen using a steel mortar and pestle.
- the powdered tissue was homogenised in 4 volumes of Buffer A (20 mM sodium phosphate, pH 6.5, containing 0.32M sucrose, 1 mM dithiothreitol and 50 ⁇ M NADPH) with an Ultra-Turrax (Janke and Kunkel GmBH & Co., Staufen i.BR., Germany).
- the homogenate was centrifuged at 500 G for 5 minutes, to remove large particles of tissue, and the supernatant was then centrifuged at 100,000 G for 1 hour.
- the resulting pellet was dispersed in Buffer A (1 ml per g of prostate tissue originally used) with the Ultra-Turrax homogeniser. This particulate preparation was then filtered through 2 layers of cheesecloth and the filtrate was stored as 1 ml samples at -70° C.
- reaction mixture was incubated at 37° C. for 30 minutes and then quenched by addition with vigorous mixing of 2 ml of ethyl acetate containing 20 ⁇ g each of testosterone and 5 ⁇ -dihydrotestosterone as carriers.
- the aqueous and organic layers were separated by centrifugation at 2000 G for 10 minutes.
- the organic layer was transferred to a second test tube and evaporated to dryness under nitrogen.
- the residue was dissolved in 50-80 ⁇ l of absolute ethanol and spotted onto a silica gel 60 F254 TLC plate (E. Merck, Darmstadt, Germany) and developed in chloroform:acetone (185:15).
- the radiochemical content in the bands of the substrate (testosterone) and the product (5 ⁇ -dihydrotestosterone) were determined with a RITA Radio TLC Analyser (Raytest Instruments Ltd., Sheffield, U.K.). The percent of recovered radiolabel converted to 5 ⁇ -dihydrotestosterone was calculated and used to determine enzyme activity. All incubations were conducted so that no more than 15% of substrate (testosterone) was converted to product.
- the compounds of the formula (I) may be tested for potency in inhibiting steroid 5 ⁇ -reductase activity in human prostate adenocarcinomas using cell lines DU145 and HPC36M.
- inhibitory potency against 5 ⁇ -reductase the following procedure was employed: Human prostate adenocarcinoma cell lines were grown in Dulbecco's Modified Eagles medium (DMEM) containing 5% serum. The cells were recovered from the medium by centrifugation, washed in serum free DMEM and suspended at 5-10 ⁇ 10 6 cells/ml. in serum free medium.
- DMEM Dulbecco's Modified Eagles medium
- test tube 10 ⁇ l of 3 H!-testosterone (1 ⁇ Ci, 20 pmol) dissolved in ethanol (Du Pont, NEN Research Products, Stevenage, U.K.) and 5 ⁇ l of an ethanol solution of a compound of the formula (I).
- ethanol Du Pont, NEN Research Products, Stevenage, U.K.
- 5 ⁇ l of an ethanol solution of a compound of the formula (I) The ethanol was evaporated under nitrogen and the testosterone and the compound redissolved in 0.25 ml of serum free medium containing 0.25 ⁇ mol NADPH.
- the mixture was warmed to 37° C. and the reaction started by addition of 0.25 ml of cell suspension (1.2-2.5 ⁇ 10 6 cells). The reaction mixture was incubated at 37° C.
- the radiochemical content in the bands of the substrate (testosterone) and the product (5 ⁇ -dihydrotestosterone) was determined with a RITA Radio TLC Analyser (Raytest Instruments Ltd., Sheffield, U.K.). The percentage of recovered radiolabel converted to 5 ⁇ -dihydrotestosterone was calculated and used to determine enzyme activity. All incubations were conducted so that no more than 15% of substrate (testosterone) was converted to product.
- the compounds of the formula (I) can be administered alone, but will generally be administered in admixture with a pharmaceutical carrier selected with regard to the intended route of administration and standard pharmaceutical practice.
- a pharmaceutical carrier selected with regard to the intended route of administration and standard pharmaceutical practice.
- they can be administered orally in the form of tablets containing such excipients as starch or lactose, or in capsules or ovules either alone or in admixture with excipients, or in the form of elixirs, solutions of suspensions containing flavouring or colouring agents.
- They can be injected parenterally, for example, intravenously, intramuscularly or subcutaneously.
- parenteral administration they are best used in the form of a sterile aqueous solution which may contain other substances, for example, enough salts or glucose to make the solution isotonic with blood.
- the daily dosage level of the compounds of the formula (I) will be from 0.01 to 20 mg/kg (in single or divided doses) and preferably will be from 0.1 to 10 mg/kg except for the treatment of human prostate adenocarcinomas where doses of up to 20 mg/kg may be used.
- tablets or capsules of the compounds will contain from 5 mg to 0.5 g of active compound for administration singly or two or more at a time, as appropriate.
- the physician in any event will determine the actual dosage which will be most suitable for an individual patient and it will vary with the age, weight and response of the particular patient.
- the above dosages are exemplary of the average case; there can, of course, be individual instances where higher or lower dosage ranges are merited, and such are within the scope of this invention.
- the compounds of the formula (I) can be administered in the form of a suppository or pessary, or they may be applied topically in the form of a lotion, solution, cream, ointment or dusting powder.
- they can be incorporated into a cream consisting of an aqueous emulsion of polyethylene glycols or liquid paraffin; or they can be incorporated, at a concentration between 1 and 10%, into an ointment consisting of a white wax or white soft paraffin base together with such stabilizers and preservatives as may be required.
- the compounds of the formula (I) may also be administered together with an ⁇ -antagonist (e.g. prazosin or doxazosin), an antiandrogen (e.g. flutamide) or an aromatase inhibitor (e.g. atamestane), particularly for the curative or prophylactic treatment of benign prostatic hypertrophy.
- an ⁇ -antagonist e.g. prazosin or doxazosin
- an antiandrogen e.g. flutamide
- an aromatase inhibitor e.g. atamestane
- composition comprising a compound of the formula (I), or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable diluent or carrier;
- a method of treatment of a human to cure or prevent acne vulgaris, alopecia, seborrhoea, female hirsutism, benign prostatic hypertrophy male pattern baldness or a human prostate adenocarcinoma which comprises treating said human with an effective amount of a compound of the formula (I) or with a pharmaceutically acceptable salt or composition thereof;
- the above racemic product (514 mg) was resolved into the component enantiomers by passage through a Chiralpak AD (Trade Mark) semi-preparative HPLC column eluting with 85:15 hexane/ethanol at a flow rate of 12 ml/min.
- the product was resolved batchwise using portions of 40 mg of product in 3 ml eluant (x 10) and 38 mg of product in 3 ml eluant (x 3).
- the compound of part (c) (3.12 g) was dissolved in toluene (15 ml) and treated with pyridine (0.9 g). This mixture was slowly added to a solution of thionyl chloride (1.2 g) in toluene (15 ml). After stirring for one hour the mixture was filtered and the filtrate evaporated to provide the acid chloride as an oil which was used directly in the next stage.
- the title compound was prepared by a similar method to that of Preparation 5 using the compound of Example 51 as the starting material.
- the title compound was prepared by a similar procedure to that of Preparation 5 using the compound of Example 52 as the starting material.
- Example 4 The compound of Example 4 was administered orally to mice up to a dose of 1000 mg/kg and the animal showed normal appearance and behaviour throughout the duration of the study.
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Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
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GB9204365 | 1992-02-28 | ||
GB929204365A GB9204365D0 (en) | 1992-02-28 | 1992-02-28 | Indoles |
PCT/EP1993/000380 WO1993017014A1 (en) | 1992-02-28 | 1993-02-16 | Indole derivatives as steroid 5 alpha-reductase inhibitors |
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US5767139A true US5767139A (en) | 1998-06-16 |
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US08/256,734 Expired - Fee Related US5767139A (en) | 1992-02-28 | 1993-02-16 | Indoles which have steroid 5-α reductase inhibitory activity |
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US (1) | US5767139A (da) |
EP (1) | EP0628040B1 (da) |
JP (1) | JP2540016B2 (da) |
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CN (1) | CN1079465A (da) |
AT (1) | ATE164376T1 (da) |
AU (1) | AU3497793A (da) |
BR (1) | BR9305991A (da) |
CA (1) | CA2117610C (da) |
CZ (1) | CZ207794A3 (da) |
DE (1) | DE69317651T2 (da) |
DK (1) | DK0628040T3 (da) |
ES (1) | ES2115053T3 (da) |
FI (2) | FI943931A (da) |
GB (1) | GB9204365D0 (da) |
HR (1) | HRP930227A2 (da) |
HU (1) | HUT71126A (da) |
IL (1) | IL104816A0 (da) |
MX (1) | MX9301112A (da) |
NO (1) | NO943187L (da) |
RU (1) | RU94042391A (da) |
SK (1) | SK100894A3 (da) |
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Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2000007590A1 (en) * | 1998-08-03 | 2000-02-17 | Eli Lilly And Company | INDOLE sPLA2 INHIBITORS |
US6069156A (en) * | 1995-04-10 | 2000-05-30 | Fujisawa Pharmaceutical Co., Ltd. | Indole derivatives as cGMP-PDE inhibitors |
US6335359B1 (en) * | 1999-07-16 | 2002-01-01 | Societe L'oreal S.A. | Indolecarboxylic compounds for treating seborrhea and complications thereof |
US6541507B1 (en) * | 1999-07-16 | 2003-04-01 | Societe L'oreal S.A. | Indolecarboxylic compounds for inducing/stimulating hair growth and/or retarding hair loss |
WO2004041782A1 (en) * | 2002-11-07 | 2004-05-21 | Akzo Nobel N.V. | Indoles useful in the treatment of androgen-receptor related diseases |
US20060128722A1 (en) * | 2002-11-07 | 2006-06-15 | Akzo Nobel N.V. | Indoles useful in the treatment of androgen-receptor related diseases |
US7812036B2 (en) | 2004-04-23 | 2010-10-12 | N.V. Organon | Androgens |
Families Citing this family (6)
Publication number | Priority date | Publication date | Assignee | Title |
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IL109728A0 (en) * | 1993-05-28 | 1994-08-26 | Pfizer Res & Dev | Indoles |
ES2099007B1 (es) * | 1993-07-16 | 1997-12-01 | Pfizer Res & Dev | Derivados de indol. |
GB9317096D0 (en) * | 1993-08-17 | 1993-09-29 | Pfizer Ltd | Indoles |
GB9403516D0 (en) * | 1994-02-24 | 1994-04-13 | Pfizer Ltd | Indoles |
GB9409583D0 (en) * | 1994-05-13 | 1994-07-06 | Pfizer Ltd | Indoles |
GB201102913D0 (en) | 2011-02-18 | 2011-04-06 | Univ Birmingham | Novel therapeutic |
Citations (1)
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US5696146A (en) * | 1993-05-28 | 1997-12-09 | Pfizer Inc. | Indole derivatives as steroid 5α-reductase inhibitors |
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US3557142A (en) * | 1968-02-20 | 1971-01-19 | Sterling Drug Inc | 4,5,6,7-tetrahydro-indole-lower-alkanoic acids and esters |
PH23498A (en) * | 1984-08-06 | 1989-08-16 | Sterling Drug Inc | 3-carbonyl-1-aminoalkyl-1h-indoles,composition and use thereof |
CA2036307C (en) * | 1990-03-08 | 2002-07-09 | Susan Jean Ward | 3-arylcarbonyl-1-aminoalkyl-1h-indole-containing antiglaucoma compositions and method |
GB9011335D0 (en) * | 1990-05-21 | 1990-07-11 | Fujisawa Pharmaceutical Co | Indolebutyric acid derivatives and process for preparation thereof |
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1992
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1993
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- 1993-02-16 RU RU94042391/04A patent/RU94042391A/ru unknown
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- 1993-02-16 DK DK93903984.8T patent/DK0628040T3/da active
- 1993-02-16 JP JP5514517A patent/JP2540016B2/ja not_active Expired - Fee Related
- 1993-02-16 EP EP93903984A patent/EP0628040B1/en not_active Expired - Lifetime
- 1993-02-16 ES ES93903984T patent/ES2115053T3/es not_active Expired - Lifetime
- 1993-02-16 US US08/256,734 patent/US5767139A/en not_active Expired - Fee Related
- 1993-02-16 BR BR9305991A patent/BR9305991A/pt not_active Application Discontinuation
- 1993-02-16 AU AU34977/93A patent/AU3497793A/en not_active Abandoned
- 1993-02-22 IL IL104816A patent/IL104816A0/xx unknown
- 1993-02-24 HR HR9204365.2A patent/HRP930227A2/hr not_active Application Discontinuation
- 1993-02-26 ZA ZA931383A patent/ZA931383B/xx unknown
- 1993-02-26 MX MX9301112A patent/MX9301112A/es unknown
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- 1994-08-29 NO NO943187A patent/NO943187L/no unknown
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Patent Citations (1)
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US5696146A (en) * | 1993-05-28 | 1997-12-09 | Pfizer Inc. | Indole derivatives as steroid 5α-reductase inhibitors |
Cited By (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6069156A (en) * | 1995-04-10 | 2000-05-30 | Fujisawa Pharmaceutical Co., Ltd. | Indole derivatives as cGMP-PDE inhibitors |
WO2000007590A1 (en) * | 1998-08-03 | 2000-02-17 | Eli Lilly And Company | INDOLE sPLA2 INHIBITORS |
US6451839B1 (en) | 1998-08-03 | 2002-09-17 | Eli Lilly And Company | Indole sPLA2 inhibitors |
US6335359B1 (en) * | 1999-07-16 | 2002-01-01 | Societe L'oreal S.A. | Indolecarboxylic compounds for treating seborrhea and complications thereof |
US6541507B1 (en) * | 1999-07-16 | 2003-04-01 | Societe L'oreal S.A. | Indolecarboxylic compounds for inducing/stimulating hair growth and/or retarding hair loss |
US6548532B2 (en) | 1999-07-16 | 2003-04-15 | Societe L'oreal S.A. | Indolecarboxylic compounds for treating seborrhea and complications thereof |
WO2004041782A1 (en) * | 2002-11-07 | 2004-05-21 | Akzo Nobel N.V. | Indoles useful in the treatment of androgen-receptor related diseases |
US20060128722A1 (en) * | 2002-11-07 | 2006-06-15 | Akzo Nobel N.V. | Indoles useful in the treatment of androgen-receptor related diseases |
US7795280B2 (en) | 2002-11-07 | 2010-09-14 | N.V. Organon | Indoles useful in the treatment of androgen-receptor related diseases |
US20110065768A1 (en) * | 2002-11-07 | 2011-03-17 | Pedro Harold Han Hermkens | Non-steroidal androgens compounds |
US8124647B2 (en) * | 2002-11-07 | 2012-02-28 | N.V. Organon | Non-steroidal androgens compounds |
US7812036B2 (en) | 2004-04-23 | 2010-10-12 | N.V. Organon | Androgens |
Also Published As
Publication number | Publication date |
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IL104816A0 (en) | 1993-06-10 |
EP0628040B1 (en) | 1998-03-25 |
JP2540016B2 (ja) | 1996-10-02 |
EP0628040A1 (en) | 1994-12-14 |
FI943931A0 (fi) | 1994-08-26 |
MX9301112A (es) | 1994-07-29 |
DK0628040T3 (da) | 1998-04-27 |
CA2117610A1 (en) | 1993-09-02 |
ZA931383B (en) | 1994-08-26 |
ES2115053T3 (es) | 1998-06-16 |
RU94042391A (ru) | 1996-08-10 |
CA2117610C (en) | 2000-07-18 |
JPH07500347A (ja) | 1995-01-12 |
FI20001771A (fi) | 2000-08-09 |
NO943187D0 (no) | 1994-08-29 |
SK100894A3 (en) | 1995-04-12 |
HUT71126A (en) | 1995-11-28 |
CN1079465A (zh) | 1993-12-15 |
KR950700287A (ko) | 1995-01-16 |
NO943187L (no) | 1994-09-13 |
AU3497793A (en) | 1993-09-13 |
WO1993017014A1 (en) | 1993-09-02 |
HRP930227A2 (en) | 1996-10-31 |
ATE164376T1 (de) | 1998-04-15 |
DE69317651T2 (de) | 1998-07-09 |
FI943931A (fi) | 1994-08-26 |
GB9204365D0 (en) | 1992-04-08 |
BR9305991A (pt) | 1997-10-21 |
DE69317651D1 (en) | 1998-04-30 |
HU9402466D0 (en) | 1994-10-28 |
CZ207794A3 (en) | 1995-01-18 |
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